Certain diseases are more difficult to treat than others. For example, some cancerous tumors may occur in remote or sensitive parts of the body. Removal of these types of tumor may require extensive, invasive, and/or delicate surgeries. If all of the tumor is not removed, repeated surgeries may be required. Repeated surgery in some parts of the body dramatically increases the risk of complications. One such area is within the central nervous system (the CNS), which is protected by the blood-brain barrier.
CNS cancer is deadly, and especially difficult to treat. Approximately 23,000 new cases of brain (and other nervous system) cancer were diagnosed this past year in the U.S., and about 14,000 people die annually as a result of the disease. 36% of the diagnosed cases are gliomas and half of these are glioblastoma, an extremely aggressive cancer with poor patient prognosis.
Current therapies, such as surgery, radiation, and chemotherapy, allow for a median survival of less than 14 months. At present, the standard of care includes surgical resection of the tumor and treatment with chemotherapy or radiation. In many cases, there may be no clear division between the tumor and normal brain tissue. Thus, it is not possible, usually, to remove all the cancerous cells. There is currently no cure for gliomas and no current treatments prevent its recurrence. Glioma's resistance to therapy is due, at least in part, to the fact that chemotherapeutic drugs, administered systemically, must traverse the blood-brain barrier (BBB).
In order to avoid the need to traverse the BBB, an implantable drug delivery system has been developed. That therapy, the Gliadel® wafer, is FDA-approved for the treatment of malignant glioblastomas. Gliadel therapy involves the placement of solid, biodegradable, polymeric wafers into the tumor resection cavity. The Gliadel wafer then slowly releases a chemotherapeutic drug, carmustine (a small molecule drug), which diffuses out of the wafer and into the surrounding tissues. Over 20,000 patients have had this treatment since it was launched in 1997; unfortunately it is associated with little improvement in survival. Poor efficacy of Gliadel is likely due to the cancer cells' abilities to overcome the effect of this therapy via expression of DNA repair enzymes.
Drugs directed to specific molecular targets, rather than nonspecific chemotherapeutic drugs such as carmustine may aid in treating individual cancers. For example, glioblastomas are highly angiogenic, meaning they encourage epithelial cells to form blood vessels that then help to feed the cancer cells. To do this, gliomas produce large amounts of a protein called Vascular Endothelial Growth Factor, or VEGF, that stimulates angiogenesis. Bevacizumab (Avastin), an anti-VEGF antibody targets angiogenesis by binding VEGF. Bevacizumab is FDA-approved for treating glioblastoma. Results of this therapy are promising, but the prognosis remains poor. Specifically, phase I and II clinical trials involving intravenous administration of Bevacizumab show that some patients have responded sufficiently to extend life expectancy several months. Poor prognosis likely stems from the need for repeated injections of antibody, due to rapid clearance of the antibody from the body. Additionally, antibodies delivered intravenously must, like other systemically delivered therapies, cross the blood-brain barrier, which is not likely to result in high concentration within the CNS.
While antibody-based treatment of tumors shows great clinical promise, the use of therapeutic antibodies for brain and other CNS cancers remains a challenge. This is because systemic (intravenous) delivery of antibodies is difficult since the therapeutic antibodies must cross the blood-brain barrier, which normally excludes large molecules. Thus, in order to treat CNS diseases by systemic administration of therapeutic agents, repeated injections, usually, in large doses are required. In the case of therapeutic antibodies, efficacy is further hindered by rapid clearance from the body.
What is needed is an approach that can deliver therapeutic agents to a localized area, for example within the brain or CNS, wherein delivery occurs over an extended period of time.